Zebrafish FOXP3 is required for the maintenance of immune tolerance

Sugimoto, Kotaro; Hui, Subhra Prakash; Sheng, Delicia Z.; Nakayama, Maki; Kikuchi, Kazu

doi:10.1016/j.dci.2017.03.023

Cited by 56 publications

(47 citation statements)

References 33 publications

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“…Genome duplication created surplus copies of regulatory factors, but wiring these into a genetic circuitry for regulatory T cells must have taken considerable evolutionary time, and each improvement in regulatory function could further potentiate the evolution of the effector components of Darwinian immunity. Of note, the deletion of Foxp3 in zebrafish results in only a moderate inflammatory phenotype (in contrast to the fatal autoimmune disease observed in Foxp3‐deficient mice) (Sugimoto et al, ), which is compatible with the view that the capacity of both effector and regulatory immune mechanisms has improved gradually during the evolution of vertebrates.…”

Section: The Origin Of Darwinian Immunity In Vertebratesmentioning

confidence: 57%

An evolutionary perspective on the systems of adaptive immunity

et al. 2017

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We propose an evolutionary perspective to classify and characterize the diverse systems of adaptive immunity that have been discovered across all major domains of life. We put forward a new function-based classification according to the way information is acquired by the immune systems: Darwinian immunity (currently known from, but not necessarily limited to, vertebrates) relies on the Darwinian process of clonal selection to 'learn' by cumulative trial-and-error feedback; Lamarckian immunity uses templated targeting (guided adaptation) to internalize heritable information on potential threats; finally, shotgun immunity operates through somatic mechanisms of variable targeting without feedback.We argue that the origin of Darwinian (but not Lamarckian or shotgun) immunity represents a radical innovation in the evolution of individuality and complexity, and propose to add it to the list of major evolutionary transitions. While transitions to higher-level units entail the suppression of selection at lower levels, Darwinian immunity re-opens cell-level selection within the multicellular organism, under the control of mechanisms that direct, rather than suppress, cell-level evolution for the benefit of the individual. From a conceptual point of view, the origin of Darwinian immunity can be regarded as the most radical transition in the history of life, in which evolution by natural selection has literally re-invented itself. Furthermore, the combination of clonal selection and somatic receptor diversity enabled a transition from limited to practically unlimited capacity to store information about the antigenic environment. The origin of Darwinian immunity therefore comprises both a transition in individuality and the emergence of a new information system -the two hallmarks of major evolutionary transitions.Finally, we present an evolutionary scenario for the origin of Darwinian immunity in vertebrates. We propose a revival of the concept of the 'Big Bang' of vertebrate immunity, arguing that its origin involved a 'difficult' (i.e. low-probability) evolutionary transition that might have occurred only once, in a common ancestor of all vertebrates. In contrast to the original concept, we argue that the limiting innovation was not the generation of somatic diversity, but the regulatory circuitry needed for the safe operation of amplifiable immune responses with somatically acquired targeting. Regulatory complexity increased abruptly by genomic duplications at the root of the vertebrate lineage, creating a rare opportunity to establish such circuitry. We discuss the selection forces that might have acted at the origin of the transition, and in the subsequent stepwise evolution leading to the modern immune systems of extant vertebrates.

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Section: The Origin Of Darwinian Immunity In Vertebratesmentioning

confidence: 57%

An evolutionary perspective on the systems of adaptive immunity

et al. 2017

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“…Studies in bony fish suggest that FOXP3 + cells act as T reg cells, perhaps as thymus-derived T reg (tT reg ) cells (also referred to as natural T reg cells) 178 . Studies carried out long ago in amphibians suggested that a population of suppressor cells was peripheralized at metamorphosis, where they were likely involved in regulating adaptive responses to newly arising adult-specific self-antigens 179 .…”

Section: T Helper Cell Subsetsmentioning

confidence: 99%

A cold-blooded view of adaptive immunity

2018

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The adaptive immune system arose 500 million years ago in ectothermic (cold-blooded) vertebrates. Classically, the adaptive immune system has been defined by the presence of lymphocytes expressing recombination-activating gene (RAG)-dependent antigen receptors and the MHC. These features are found in all jawed vertebrates, including cartilaginous and bony fish, amphibians and reptiles and are most likely also found in the oldest class of jawed vertebrates, the extinct placoderms. However, with the discovery of an adaptive immune system in jawless fish based on an entirely different set of antigen receptors — the variable lymphocyte receptors — the divergence of T and B cells, and perhaps innate-like lymphocytes, goes back to the origin of all vertebrates. This Review explores how recent developments in comparative immunology have furthered our understanding of the origins and function of the adaptive immune system.

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“…Tissue macrophages play a key role in sensing pathogenic microbiota in zebrafish 33,35 . To investigate the impact of A20 deletion on macrophage homeostasis, heterozygous A20 +/∆127 zebrafish were crossed to a macrophage reporter line whereby RFP is expressed under the control of the promotor of macrophage-expressed gene 1.1 ( mpeg1.1 ) 36 . Loss of A20 completely altered both the number and phenotype of tissue macrophages in ways consistent with increased cellular response to stimulation.…”

Section: Resultsmentioning

confidence: 99%

“…The lck:RFP (TgBAC( lck :RFP) vcc4 ) and mpeg1.1:RFP (TgBAC( mpeg1.1 :RFP) vcc7 ) reporter lines have been described previously 36 . The lymphocyte protein tyrosine kinase ( lck ) promoter targets gene expression to T cells whereas macrophage expressed gene 1.1 ( mpeg1.1 ) promoter targets gene expression to macrophages.…”

Section: Methodsmentioning

confidence: 99%

A zebrafish functional genomics model to investigate the role of human A20 variantsin vivo

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et al. 2020

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24Germline loss-of-function variation in TNFAIP3, encoding A20, has been implicated in a wide 25 variety of autoinflammatory and autoimmune conditions, with acquired somatic missense 26 mutations linked to cancer progression. Furthermore, human sequence data reveals that the A20 27 locus contains ~400 non-synonymous coding variants which are largely uncharacterised. The 28 growing number of A20 coding variants with unknown function, but potential clinical impact, 29 poses a challenge to traditional mouse-based approaches. Here we report the development of a 30 novel functional genomics approach that utilises the new A20-deficient zebrafish (Danio rerio) 31 model to investigate the impact of TNFAIP3 genetic variants in vivo. Similar to A20-deficient 32 mice, A20-deficient zebrafish are hyper-responsive to inflammatory triggers and exhibit 33 spontaneous early lethality. While ectopic addition of human A20 rescued A20-null zebrafish from 34 lethality, missense mutations at two conserved A20 residues, S381A and C243Y reversed this 35 protective effect. Ser381 represents a phosphorylation site important for enhancing A20 activity 36 that is abrogated by its mutation to alanine, or by a C243Y mutation that associates with human 37 autoimmune disease. These data reveal an evolutionarily conserved role for A20, but also 38 demonstrate how a zebrafish functional genomics pipeline can be utilized to investigate the in vivo 39 significance of medically relevant TNFAIP3 gene variants. This approach could be utilised to 40 investigate genetic variation for other conserved genes. 41 42 45activation 2-6 . The medical importance of A20's role in dampening NF-κB is highlighted by cases 46 of germline A20 loss-of-function mutations in humans who present with severe autoinflammatory 47 disease 7,8 , and by the impact of A20 deletion in mice which results in spontaneous and widespread 48 NF-κB activation, multi-organ inflammation and premature lethality 1,9 . The emergence of A20 49 mutations and coding variants as causal genetic factors driving human disease 10,11 highlight the 50 need to better understand A20's functional domains controlling inflammation in vivo. 51 52 A20 suppresses NF-κB signalling with inhibitory activity against key molecular substrates 53 including signalling molecules TNF receptor-associated factor 6 (TRAF6) 9 , receptor interacting 54 protein 1 (RIP1) 12,13 , and the IκB kinase complex (IKK) 14 . The A20 ovarian-tumour (OTU) 55 domain exhibits deubiquitinating editing (DUB) activity cantered on Cys103, which cleaves 56 activating K63-linked ubiquitin chains from RIPK1, TRAF6 and NEMO to terminate NF-κB 57 signalling 9,12,13,15 . The A20 zinc finger 4 (ZnF4) exhibits E3 ligase activity, adding K48-linked 58 ubiquitin chains to RIPK1, triggering RIPK1 proteolysis 12,16 . In addition, the C-terminal ZnF7 59 domain of A20 binds linear ubiquitin to non-catalytically suppress NF-κB activity 17 . A20 is 60 regulated at the level of gene transcription 6 , whereby NF-κB activation induces TNFAIP3 61 expressi...

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Zebrafish FOXP3 is required for the maintenance of immune tolerance

Cited by 56 publications

References 33 publications

An evolutionary perspective on the systems of adaptive immunity

An evolutionary perspective on the systems of adaptive immunity

A cold-blooded view of adaptive immunity

A zebrafish functional genomics model to investigate the role of human A20 variantsin vivo

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